The present invention relates to novel compounds, pharmaceutical compositions containing them, to processes for their preparation and to the uses thereof. More particularly, this invention relates to compounds that exhibit agonist activity to peroxisome proliferator-activated receptor gamma enabeling them to be useful in modulation of blood glucose and the increase of insulin sensitivity in mammals
Type II or Non-Insulin Dependent Diabetes Mellitus (NIDDM) involves abnormal glucose metabolism characterized by defects in three organ systems, namely, liver (increased glucose production by the liver due to increased levels of glucagon and free fatty acids as well as recycling of gluconeogenic precursors lactate and pyruvate), pancreas (impaired glucose-induced insulin secretion leading to fasting hyperglycemia) and peripheral target tissues such as the skeletal muscle (resistance to the action of insulin due to insulin receptor or post receptor defects).
The sulfonyl urea class of drugs exert their anti-hyperglycemic effects by stimulating the release of insulin from the xcex2 cells of the pancreas. These however have undesirable toxic effects such as fatigue of xcex2 cells with long term use, obesity and incidence of hypoglycemia. The biguanides act on insulin resistance by reduced glucose absorption, decreased glucuneogenesis, increased anorexia, enhance insulin binding to its receptor and increased glucose transport in fat and muscle. Thus the treatment of insulin resistance and/or suppression of increased hepatic glucose production in type II diabetes is an attractive area of drug development.
The thiazolidinedione class of drugs (troglitazone), was developed for its potent lipid-peroxide-lowering activity which improved hyperglycemia, hyperinsulinemia and hypertriglceridemia in the diabetic KK mice (a genetically insulin resistance model of type II diabetes). Troglitazone also increased glucose uptake in adipocytes thus increasing insulin sensitivity and responsiveness.
Three cell lines have been used to assess the effects of thiazolidinediones: NIH 3T3 mouse fibroblast that differentiates into insulin responsive adipocytes (fat cell model), HepG2, a human hepatoma cell line (liver cell model) and L6 rat myocytes (muscle cell model). In the first model the xe2x80x9cglitazonesxe2x80x9d increase the differentiation into adipocytes and increase the expression of fat cell-specific genes like lipoprotein lipase, aP2, acyl CoA synthase and adipsin thereby contributing to the stimulation of triglyceride clearance. In the latter model and in fat cells the thiazolidinediones increase the expression of glucose transporter, GLUT4, thereby exerting an insulin-sensitizing effect by stimulating basal and insulin-stimulated glucose uptake. Recently, it has been demonstrated that the thiazolidinediones and prostanoids of the J2 series are ligands for the Peroxisome Proliferator Activated Receptors (members of the steroid/thyroid hormone receptor super family). Members of this family include the alpha, gamma and delta, of which the PPARg receptor has been shown to be preferentially expressed in preadipocytes and immune system. A general model for activation of PPARgamma by thiazolidinediones include a ligand induced conformational change leading to the displacement of a xe2x80x9ccorepressorxe2x80x9d or allowing the binding of a coactivator thereby facilitating heterodimerization with another nuclear receptor RXR. The activated heterodimer interacts with specific DNA sequences xe2x80x9cTGACCT-N-TGACCTxe2x80x9d or PPREs (the Peroxisome Proliferator Response Elements) to activate transcription of thiazolidinedione responsive genes (such as lipoprotein lipase), either directly or by interacting with sites that overlap insulin responsive sequences (IRS) (such as in the glucokinase promoter). The PPREs have been identified in the promoters of a number of genes for proteins involved in the regulation of lipid metabolism suggesting that PPARgamma is an attractive therapeutic target for obesity and NIDDM.
The present invention relates to heterocycle derivatives which are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) selective agonists and such are useful in the modulation of blood glucose and the increase of insulin sensitivity in mammals. This activity of the piperazine derivatives of the invention make them particularly useful in the treatment of those conditions selected from the group consisting of diabetes, atherosclerosis, hyperglycemia, hyperlipidemia, obesity, syndrome X, insulin resistance, hypertension, heart failure and cardiovascular disease in mammals.
The present invention relates to the compounds of formula (I) below and its derivatives, pharmaceutically acceptable salts thereof, which are non-thiazolidinedione PPARgamma agonists so that they might surmount the problems associated with the known thiazolidinediones and thus offer an advantage as a therapeutic agent in treating diseases described above.
The present invention provides novel compounds of Formula (I) or pharmaceutical 
acceptable salts thereof, wherein the broken line represents an optional double bond;
X is H, O, S;
A is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)mxe2x80x94;
B is O, S, NR6, wherein R6 is H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl and C3-C6 cycloalkyl;
n is 0 or 1;
m is 1 or 2;
G is C3-C10 cycloalkyl, C4-C10 cycloalkenyl, saturated C3-C10 heterocyclyl, C3-C10 cycloalkyl-C1-C3 alkyl, C4-C10 cycloalkenyl-C1-C3 alkyl, saturated C3-C10 heterocyclyl-C1-C3 alkyl, said cycloalkyl, cycloalkenyl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of Rs, wherein heterocyclyl contains 1 to 4 heteroatoms which may be nitrogen, sulfur or oxygen atom;
R1 is hydrogen, hydroxy, thio, nitro, cyano, azido, amino, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 alkenyl, C1-C6 alkenyloxy, C1-C6 alkenylamino, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C3-C8 cycloalkylamino, C3-C8 cycloalkylthio, C1-C6 alkylcarbonylamino, C3-C8 cycloalkylcarbonylamino, C5-C10 aryl, C5-C10 heteroaryl or C5-C10 saturated heteroaryl; said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of Rs;
R2, R3, R4 and R5 independently are H, trifluoromethyl, C5-C10 aryl, C5-C10 heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, saturated C5-C10 heteroaryl, C5-C10 aryl-C1-C10 alkyl, C5-C10 heteroaryl-C1-C10 alkyl, COR7, CO2R7, CONR7R8, SO2NR7R8, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of Rs;
R7 and R8 independently are H, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of Rs;
Rs represents a member selected from the group consisting of halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, OCF3 acyl, aryl, heteroaryl, S(O)R8, xe2x95x90N(OR8), SO2R8, COOR8, xe2x80x94CONR7R8, xe2x80x94C1-C6alkylCONR7R8, C1-C6alkyloxy, aryloxy, arylC1-C6alkyloxy, thio, C1-C6alkylthio, arylthio, arylC1-C6alkylthio, NR7R8, C1-C6alkylamino, arylamino, arylC1-C6alkylamino, di(arylC1-C6alkyl)amino, C1-C6alkylcarbonyl, arylC1-C6alkylcarbonyl, C1-C6alkylcarboxy, arylC1-CC6alkylcarboxy, xe2x80x94NR7CO2R8, xe2x80x94NR7CO2R8, xe2x80x94NR7SO2R8, xe2x80x94CONR7R8, xe2x80x94SO2NR7R8, xe2x80x94OCONR7R8, xe2x80x94C1-C6alkylaminoCONR7R8, arylC1-C6alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, or a saturated or partial saturated cyclic 5,6 or 7 membered amine or lactam; said aryl, and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-C6alkyl; wherein R7 and R8 are defined as above.
As used herein, the xe2x80x9cxe2x80x94xe2x80x9d (e.g. xe2x80x94COR7 which indicates the carbonyl attachment point to the scaffold) signifies a stable covalent bond, certain preferred points of attachment points being apparent to those skilled in the art.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d include fluorine, chlorine, bromine, and iodine.
The term xe2x80x9calkylxe2x80x9d includes C1-C12 saturated aliphatic hydrocarbon groups unless otherwise defined. It may be straight or branched alkyl groups. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached. The alkyl group may be substituted by one or more hydroxy, halo, cycloalkyl, cycloalkenyl or heterocyclyl. Examplary alkyl groups include methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and the like.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
The term xe2x80x9calkenylxe2x80x9d includes C2-C12 aliphatic hydrocarbon groups containing at least one carbon to carbon double bond and which may be straight or branched unless otherwise defined. Preferably one carbon to carbon double bond is present, up to four non-aromatic carbon to carbon double bond may present. Branched means one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, and cyclohexylbutenyl, decenyl, and the like. As described above with respect to alkyl, the straight, branched and cyclic portion of the alkenyl group may contain double bonds and may be substituted when substituted alkenyl group is provided.
The term xe2x80x9calkynylxe2x80x9d includes C2-C12 aliphatic hydrocarbon groups containing at least one carbon to carbon triple bond and which may be straight or branched unless otherwise defined. Preferably one carbon to carbon double bond is present, up to carbon to carbon triple bond may present. Branched means one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. xe2x80x9cLower alkynylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. For example, this definition shall include but is not limited to ethynyl, propynyl, butynyl, and the like. As described above with respect to alkyl, the straight, branched and cyclic portion of the alkynyl group may contain triple bonds and may be substituted when substituted alkynyl group is provided.
The term xe2x80x9ccycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 atoms. Preferred monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and halocyclohexyl and cycloheptyl; More preferred is cyclohexyl. The cycloalkyl group may be substituted by one or more halo, methylene (CH2xe2x95x90), alkyl, fused aryl and fused heteroaryl.
The term xe2x80x9ccycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 atoms. Preferred monocyclic cycloalkyl rings include cyclopentenyl, cyclohexenyl and halocyclohexenyl and cycloheptenyl; More preferred is cyclohexenyl. The cycloalkyl group may be substituted by one or more halo, methylene (CH2xe2x95x90), alkyl, fused aryl and fused heteroaryl.
The term xe2x80x9cheterocyclylxe2x80x9d means an about 4 to about 10 member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen or sulfur. The heterocyclyl may be optionally substituted by one or more alkyl group substituents. Examplary heterocyclyl moieties include quinuclidine, pentamethylenesulfide, tetrahedropyranyl, tetrahydrothiophenyl, pyrrolidinyl or tetrahydrofuranyl.
The term xe2x80x9calkyloxyxe2x80x9d (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term xe2x80x9calkyloxyalkylxe2x80x9d represents an xe2x80x9calkyloxyxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9caryloxyxe2x80x9d (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term xe2x80x9carylalkyloxyxe2x80x9d (e.g. phenethyloxy, naphthylmethyloxy and the like) represents an xe2x80x9carylalkylxe2x80x9d group as defined below attached through an oxygen bridge.
The term xe2x80x9carylalkyloxyalkylxe2x80x9d represents an xe2x80x9carylalkyloxyxe2x80x9d group as defined above attached through an xe2x80x9calkylxe2x80x9d group defined above having the indicated number of carbon atoms.
The term xe2x80x9carylthioxe2x80x9d (e.g. phenylthio, naphthylthio and the like) represents an xe2x80x9carylxe2x80x9d group as defined below attached through a sulfur bridge.
The term xe2x80x9calkyloxycarbonylxe2x80x9d (e.g. methylformate, ethylformiat and the like) represents and xe2x80x9calkyloxyxe2x80x9d group as defined above attached through a carbonyl group.
The term xe2x80x9caryloxycarbonylxe2x80x9d (e.g. phenylformate, 2-thiazolylformiat and the like) represents an xe2x80x9caryloxyxe2x80x9d group as defined above attached through a carbonyl group.
The term xe2x80x9carylalkyloxycarbonylxe2x80x9d (e.g. benzylformate, phenylethylformiat and the like) represents an xe2x80x9carylalkyloxyxe2x80x9d group as defined above attached through a carbonyl group.
The term xe2x80x9calkyloxycarbonylalkylxe2x80x9d represents an xe2x80x9calkyloxycarbonylxe2x80x9d group as defined above attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkyloxycarbonylalkylxe2x80x9d represents an xe2x80x9carylalkyloxycarbonylxe2x80x9d group as defined above attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms.
The term xe2x80x9calkylthioxe2x80x9d (e.g. methylthio, ethylthio, propylthio, cyclohexylthio and the like) represents an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
The term xe2x80x9carylalkylthioxe2x80x9d (e.g. phenylmethylthio, phenylethylthio, and the like) represents an xe2x80x9carylalkylxe2x80x9d group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
The term xe2x80x9calkylthioalkylxe2x80x9d represents an xe2x80x9calkylthioxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkylthioalkylxe2x80x9d represents an xe2x80x9carylalkylthioxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9calkylaminoxe2x80x9d (e.g. methylamino, diethylamino, butylamino, N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, pyrrolidinyl, piperidinyl, and the like) represents one or two xe2x80x9calkylxe2x80x9d groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups may be taken together with the nitrogen to which they are attached forming a cyclic or bicyclic system containing 3 to 11 carbon atoms and 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C1-C6alkyl, aryl, arylC1-C6alkyl, hydroxy, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, NRR8, C1-C6alkylaminoC1-C6alkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R and R8 are defined as above.
The term xe2x80x9carylalkylaminoxe2x80x9d (e.g. benzylamino, diphenylethylamino and the like) represents one or two xe2x80x9carylalkylxe2x80x9d groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two xe2x80x9carylalkylxe2x80x9d groups may be taken together with the nitrogen to which they are attached forming a cyclic or bicyclic system containing 3 to 11 carbon atoms and 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C1-C6alkyl, aryl, arylC1-C6alkyl, hydroxy, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, NRR8, C1-C6alkylaminoC1-C6alkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R7 and R8 are defined as above.
The term xe2x80x9calkylaminoalkylxe2x80x9d represents an xe2x80x9calkylaminoxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkylaminoalkylxe2x80x9d represents an xe2x80x9carylalkylaminoxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkylxe2x80x9d (e.g. benzyl, phenylethyl) represents an xe2x80x9carylxe2x80x9d group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
The term xe2x80x9calkylcarbonylxe2x80x9d (e.g. cyclooctylcarbonyl, pentylcarbonyl) represents an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term xe2x80x9carylalkylcarbonylxe2x80x9d (e.g. phenylcyclopropylcarbonyl, phenylethylcarbonyl and the like) represents an xe2x80x9carylalkylxe2x80x9d group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term xe2x80x9calkylcarbonylalkylxe2x80x9d represents an xe2x80x9calkylcarbonylxe2x80x9d group attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkylcarbonylalkylxe2x80x9d represents an xe2x80x9carylalkylcarbonylxe2x80x9d group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term xe2x80x9calkylcarboxyxe2x80x9d (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an xe2x80x9calkylcarbonylxe2x80x9d group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term xe2x80x9carylalkylcarboxyxe2x80x9d (e.g. benzylcarboxy, phenylcyclopropylcarboxy and the like) represents an xe2x80x9carylalkylcarbonylxe2x80x9d group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term xe2x80x9calkylcarboxyalkylxe2x80x9d represents an xe2x80x9calkylcarboxyxe2x80x9d group attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms.
The term xe2x80x9carylalkylcarboxyalkylxe2x80x9d represents an xe2x80x9carylalkylcarboxyxe2x80x9d group attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms.
The term xe2x80x9calkylcarbonylaminoxe2x80x9d (e.g. hexylcarbonylamino, cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents an xe2x80x9calkylcarbonylxe2x80x9d group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term xe2x80x9carylalkylcarbonylaminoxe2x80x9d (e.g. benzylcarbonylamino and the like) represents an xe2x80x9carylalkylcarbonylxe2x80x9d group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term xe2x80x9calkylcarbonylaminoalkylxe2x80x9d represents an xe2x80x9calkylcarbonylaminoxe2x80x9d group attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term xe2x80x9carylalkylcarbonylaminoalkylxe2x80x9d represents an xe2x80x9carylalkylcarbonylaminoxe2x80x9d group attached through an xe2x80x9calkylxe2x80x9d group as defined above having the indicated number of carbon atoms. The nitrogen atom may itself be substituted with an alkyl or aryl group.
The term xe2x80x9calkylcarbonylaminoalkylcarbonylxe2x80x9d represents an xe2x80x9calkylcarbonylaminoalkylxe2x80x9d group attached through a carbonyl group. The nitrogen atom may be further substituted with an xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d group.
The term xe2x80x9carylxe2x80x9d represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. Aryl groups may likewise be substituted with 0-3 groups selected from Rs. The definition of aryl includes but is not limited to phenyl, biphenyl, indenyl, fluorenyl, naphthyl (1-naphtyl, 2-naphthyl).
Heteroaryl is a group containing from 5 to 10 atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are nitrogen, and 0-1 of which are oxygen or sulfur, said heteroaryl groups being substituted with 0-3 groups selected from Rs. The definition of heteroaryl includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isopuinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydrobenzo[b]furanyl (2-(2,3-dihydrobenzo[b]furanyl), 3-(2,3-dihydrobenzo[b]furanyl), 4-(2,3-dihydrobenzo[b]furanyl), 5-(2,3-dihydrobenzo [b]furanyl), 6-(2,3-dihydrobenzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydrobenzo[b]thiophenyl (2-(2,3-dihydrobenzo [b]thiophenyl), 3-(2,3-dihydrobenzo[b]thiophenyl), 4-(2,3-dihydrobenzo[b]thiophenyl), 5-(2,3-dihydrobenzo[b]-thiophenyl), 6-(2,3-dihydrobenzo[b]thiophenyl), 7-(2,3-dihydrobenzo[b]thiophenyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepinyl (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepin-2-yl, 5H-dibenz[b,f]azepin-3-yl, 5H-dibenz[b,f]azepin-4-yl, 5H-dibenz[b,f]azepie-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepinyl (10,11-dihydro-5H-dibenz[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-5-yl), piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), phenylpyridyl (2-phenylpyridyl, 3-phenylpyridyl, 4-phenylpyridyl), phenylpyrimidinyl (2-phenylpyrimidinyl, 4-phenylpyrimidinyl, 5-phenylpyrimidinyl, 6-phenylpyrimidinyl), phenylpyrazinyl, phenylpyridazinyl (3-phenylpyridazinyl, 4-phenylpyridazinyl, 5-phenylpyridazinyl).
The tern xe2x80x9carylcarbonylxe2x80x9d (e.g. 2-thiophenylcarbonyl, 3-methoxyanthrylcarbonyl, oxazolylcarbonyl) represents an xe2x80x9carylxe2x80x9d group as defined above attached through a carbonyl group.
The term xe2x80x9carylalkylcarbonylxe2x80x9d (e.g. (2,3-dimethoxyphenyl)propylcarbonyl, (2-chloronaphthyl)pentenylcarbonyl, imidazolylcyclopentylcarbonyl) represents an xe2x80x9carylalkylxe2x80x9d group as defined above wherein the xe2x80x9calkylxe2x80x9d group is in turn attached through a carbonyl.
The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
Pharmaceutically acceptable salts of the compounds of formula 1, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as xe2x80x94COOH or xe2x80x94P(O)(OH)2, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, acetate, oxalate, maleate, fumarate, citrate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
Also, in the case of the xe2x80x94COOH or xe2x80x94P(O)(OH)2 being present, pharmaceutically acceptable esters can be employed (e.g. methyl, tert-butyl, pivaloyloxymethyl, and the like), and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
Prefered compounds for use according to the invention are selected from the following species:
Methyl[1-cyclohexylcarbamoyl-4-benzyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetate;
[1-Cyclohexylcarbamoyl-4-benzyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetic acid;
N-Tetrahydrofurfuryl[1-cyclohexylcarbamoyl-4-benzyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-piperazin-2-yl]-acetamide;
[1-Cyclohexylcarbamoyl-4-benzyl-6-(S)-benzyl-5-oxo-piperazin-2-yl]-acetic acid;
N-Methyl[1-cyclohexylcarbamoyl-4-benzyl-6-(S)-benzyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl[1-cyclohexylcarbamoyl-4-(4-methoxybenzyl)-6-(S)-methylcarbamoyl-3-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(R)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(S)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(R)-[1-cyclohexylcarbamoyl-4-cyclohexylmethyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(S)-[1-cyclohexylcarbamoyl-4-cyclohexylmethyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(R)-[1-cyclohexylcarbamoyl-4-(3-pyridylmethyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(S)-[1-cyclohexylcarbamoyl-4-(3-pyridylmethyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(R)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(S)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetic acid;
(R)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetic acid;
(S)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetic acid;
N-Methyl(R)-[1-(1-piperidylcarbamoyl)-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(S)-[1-(1-piperidylcarbamoyl)-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(R)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(S)-[1-cyclohexylcarbamoyl-4-(3,4-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(R)-[1-cyclohexylcarbamoyl-4-(4-dimethylminobenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Tetrahydrofurfuryl(S)-[1-cyclohexylcarbamoyl-4-(4-dimethylminobenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
Methyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetate;
N-Methyl(R)-[1-cyclohexylmethylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(S)-[1-cyclohexylmethylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(R)-[1-cyclohexylcarbamoyl-4-benzyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(S)-[1-cyclohexylcarbamoyl-4-benzyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(R)-[1-cyclopentylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(S)-[1-cyclopentylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(R)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl(S)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(R)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(S)-[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(R)-[1-cyclohexylcarbamoyl-4-cyclohexylmethyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Butyl(S)-[1-cyclohexylcarbamoyl-4-cyclohexylmethyl6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl[1-cyclohexylcarbamoyl-4-cyclohexylmethyl-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-Methyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-butyl-5-oxo-piperazin-2-yl]-acetamide;
N-Ethyl[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
N-(2-Hydroxyethyl)[1-cyclohexylcarbamoyl-4-(3,5-dimethoxybenzyl)-6-(S)-isobutyl-5-oxo-piperazin-2-yl]-acetamide;
Preparation of Compounds
Compounds of formula 1 may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature. General methods for preparing compounds according to the invention may also be prepared as described in the schemes that follows.
Scheme 1 illustrated below, refers to the preparation of compounds of the formula (1), wherein n=1, and R3 is introduced from the corresponding amine used in the first step. The compound of formula 1-2 is prepared from a compound of formula 1-1, a 4-bromocrotonate derivative which can be reacted with an amine in an appropriate solvent (such as dichloromethane, DMF, THF, etc.). The subsequent coupling with an Fmoc amino acids or a Boc 
amino acid in the presence of DIC or EDC in a solvent, such as DMF, THF or dichloromethane, under the standard conditions gives an acylated product of formula 1-3. Removal of Fmoc protecting group can be achieved by the treatment with piperidine in DMF. A simultaneous cyclization occurs under the basic conditions to give the cyclic compounds, formula 1-4. Alternatively, Boc protecting group can be removed under the standard condition (TFA/DCM) gives a free amine derivative which then undergoes an intramolecular Michael addition in the presence of base, such as triethylamine or DIEA. Compounds of formula 1-6 are obtained by the treatment with various isocyanates in the presence of a base (DIEA, triethylamine, DMAP or pyridine).
Alternatively, the preparation of a compound of formula 1-6 from 1-4 is also achieved via an intermediate of formula 1-5 which is formed by the treatment with excess of phosgene, triphosgene, sulfonyl chloride, or their equivalents, such as carbonyldiimidazole and sulfonyldiimidazole. The subsequent formation of a urea or a sulfonamide is achieved by the treatment with an amine.
The compound of formula 1-6 is then converted to a carboxylic acid of formula 1-8 under various cleavage conditions, preferably in the presence of LiOH/THF/H2O at room temperature for 15-24 h. A compound of formula 1-9 is prepared from the compound of formula 1-8 in the presence of an appropriate alcohol and a coupling reagent (DCC/DMAP, BOP-Cl/Et3N) in an aprotic solvent at 20-30xc2x0 C., preferably at room temperature. An amide of formula 1-7 is prepared from the compound of formula 1-6 in the presence of an excess of amine. The compound of formula 1-8 can also be converted to the amide of formula 1-7 under various coupling conditions in the presence of the amine. Preferable coupling reagents are DIC and EDC in DCM or DMF.
Scheme 2 shows an alternative means for the preparation of a key intermediate of formula 1-2. A Boc-xcex1-amino aldehyde undergoes Wittig reaction by using an alkyl dialkylphosphonoacetate under standard conditions to give an xcex1,xcex2-unsaturated ester. 
Removal of the Boc protecting group gives the intermediate 1-2.
Scheme 3 shows a sequence for preparation of the corresponding piperazine analogs described as formula 3-5, 3-6, and 3-7. A reductive amination of Boc-xcex1-amino aldehyde gives a 1,2-diamine of formula 3-2. The unprotected amino group is alkylated with a 4-bromocrotonate to give a precursor 3-3. An intramolecular cyclization under the same conditions as described in 
Scheme 1 gives a piperazine intermediate. The same precedure can be followed for the preparation of ureas and sulfonamides. 
An alternative means for the preparation of these compounds according to the invention is the use of solid phase synthesis method. As shown in Scheme 4, a bromocrotonate moiety can be linked to a solid support, e.g, Wang resin, Merrifield resin, etc. Compared to the Scheme 1, the solid support can be considered as an alternative protecting group. However, a unique advantage of this approach is the intermediate from each step is not to be purified, the reaction can be pushed to completion by using the excess of the reagents (usually 5-10 equiv.). A final compound is released under an appropriate cleavage condition.
Scheme 5 shows a sequence for the preparation of a class of compounds described as formula 5-6. By the solid phase approach, An orthogonally protected Boc-Fmoc-diaminopropionate resin is selectively de-protected to release xcex2-amino group. A reductive alkylation followed by acylation with fumaric acid monoester give a compound of formula 5-3. 
Removal of the Boc group followed by cyclization give a polymer-bound piperazinone intermediate of formula 5-4. The further functional groups, such as urea and sulfonamide, can be introduced under the same conditions described above.